Project Summary/Abstract Type 2 diabetes mellitus (T2DM) is a chronic disease of epidemic proportions that is marked by insulin resistance and progressive loss of beta cell number and function. This relative insulinopenia results from a combination of beta cell dysfunction and loss of beta cell mass. Obesity is a major driver of T2DM. More than half of the patients with T2DM are obese and 86% are considered overweight or obese. Adipose tissue function and dysfunction have thus been intimately linked to the development and progression of T2DM. In our NIH funded K08 award, we identified the adipokine adipsin, which is reduced in obesity, as a critical regulator of pancreatic beta cell failure in murine models of T2DM. In this proposal, we seek to follow up on these studies and assess the possibility that prolonged adipsin treatment may be a good therapy for chronic diabetes. The proposed work will involve both in vitro experiments using pancreatic islets and in vivo analyses of mice in a type 2 diabetic model with beta cell insufficiency. We will pursue the following specific aims: 1. Determine how the adipsin/C3a pathway protects against pancreatic beta cell failure in a model of type II diabetes mellitus with beta cell failure. 2. Determine the mechanism of action of C3a-mediated protection of islet cells from cell death. These studies will shed light on novel adipose-pancreatic pathways that may ultimately lead to new treatment options for T2DM.